Stimulating signals are typically carried by acetylcholine within a nervous system synapse. Such signals may be discontinued by a specific type of cholinesterase enzymes, acetylcholinesterase, which breaks down acetylcholine. If cholinesterase inhibiting chemicals are present, they may then prevent the breakdown of acetylcholine thereby disrupting normal nervous system activity. For example, certain chemical classes of pesticides, such as organophosphates and carbamates, may result in toxic cholinesterase inhibition. Accordingly, if an individual is regularly exposed to such inhibitors, there remains a need to prophylactically or therapeutically treat such toxicity. Among other things, individuals or animals who may have been exposed to a carbamate type cholinesterase inhibitor may currently be treated with atropine, and those exposed to organophosphates may beneficially be treated with a pralidoxime antidote.
Organophosphorous nerve agents (OPNA) have been used as chemical weapons, and as noted, in pesticides, have reportedly cause an estimated 300,000 deaths per year worldwide. See, e.g., Eyer, P. et al, Toxicol. Rev. 2003, 22, 165-90. Currently, the bis-pyridinium oximes known as: (1) HLo-7 dimethylsulfate (DMS), otherwise known as 1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2,4-bis [(hydroxyimino)methyl]pyridinium dimethane sulfonate); (2) HI-6 DMS, otherwise known as (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydroxyimino)methyl]pyridinium dimethane sulfonate); and (3) obidoxime DMS, otherwise known as oxo-[[1-[[4-(oxoazaniumylmethylidene)pyridin-1-yl]methoxymethyl]pyridin-4-ylidene]methyl]azanium dimethane sulfonate, are reportedly among the most effective reactivators of OPNA inhibited acetylcholinesterase (AChE).
However, current methods to synthesize the above referenced antidotes require the use of chemical compounds which are extremely toxic and which lead to relatively large amounts of side products that are difficult to remove from the reaction media. Accordingly, a continuing need exists for more efficient pathways to produced desired reactivators of OPNA inhibited AChE.